Side view of a head silhouette in blue showing a cloud around the brain to symbolize Alzheimer's disease, which can be caused by carriage of the APOE4 allele
Credit: Naeblys/Getty Images

Lower serotonin levels may play a central role in long COVID, and possibly other post-viral cognitive syndromes, according to new research published last week in Cell. The study, led by researchers from the Perelman School of Medicine at the University of Pennsylvania, aims to explain how persistent inflammation after contracting the SARS-CoV-2 virus can cause long-term neurological symptoms. 

“Our findings may not only help to untangle some of the mechanisms that contribute to long COVID, but also provide us with biomarkers that can help clinicians diagnose patients and objectively measure their response to individual treatments,” said senior author, Maayan Levy, PhD, an assistant professor of Microbiology at Penn Medicine.

According to the CDC, “Long COVID includes a wide range of ongoing respiratory, neurologic, cardiovascular, and other symptoms that can last for weeks, months, or years following SARS-CoV-2 infection. Estimates of long COVID incidence among nonhospitalized adults with COVID-19 range from 7.5% to 41%.”

The pathophysiology of long COVID is unknown and no effective treatments have been found yet. Symptoms can last for weeks, months, or years following SARS-CoV-2 infection. Several hypotheses have been forwarded to explain the etiology of long COVID, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. 

This team proposes a mechanism that links all four hypotheses in a single pathway— serotonin reduction. Serotonin, which is primarily produced in the GI tract, plays a key role in regulating memory, sleep, digestion, wound healing, and other functions that maintain homeostasis within the body. It is also an important regulator of the vagus nerve, a system of neurons that mediate the communication between the body and the brain.

Using metabolomics and a combination of human cohort studies, animal models of viral infection, and organoid cultures, the team showed that the presence of viral RNA and downstream interferon responses cause a decrease in serotonin after the disease.

Viral infection and type I interferon-driven inflammation, they report,  reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan, platelet hyperactivation and thrombocytopenia that impacts serotonin storage, and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction then impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. 

The researchers determined that a subset of patients with long COVID had traces of the SARS-CoV-2 virus in their stool samples even months after acute COVID-19 infection, which suggests that components of the virus remain in the gut of some patients long after infection. 

“Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving. Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials that address the specific causes of their long COVID symptoms, and more effectively assess their progress,” said co-senior author, Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine.

The authors took this insight one step further, to identify if replenishing tryptophan or serotonin in patients who exhibit deficiencies could treat long COVID symptoms. They demonstrated that serotonin levels could be restored, and memory impairment reversed, in small animal models through treatment with serotonin precursors or selective serotonin reuptake inhibitors (SSRIs).

“There has been some evidence to suggest that SSRIs could be effective in preventing long COVID, and our research now presents an opportunity for future studies to select specific patients for a trial who exhibit depleted serotonin, and to be able to measure response to treatment,” said co-senior author, Benjamin Abramoff, MD, MS, director of Penn Medicine’s Post-COVID Assessment and Recovery Clinic.

Also of Interest